Researchers at Johns Hopkins have evidence that curbed
activity from several key chemicals on the inner lining of
the nose are linked to chronic sinusitis that fails to
respond to the usual current treatments.
An estimated 32 million Americans know the misery of
persistent inflammation of the moist tissue that lines the
nose and sinus cavities. The result, according to the U.S.
Centers for Disease Control and Prevention, is clogged
passages and recurring infections.
Because nearly one in 10 of those treated see symptoms
return within weeks or months after drugs or surgery fails
to keep the sinus passages open, scientists have long
suspected that these resistant cases had some underlying
problem with the immune system contributing to the
ailment.
In a study to be described on Sept. 19 at the annual
scientific sessions of the American Academy of
Otolaryngology, Head and Neck Surgery, the Johns Hopkins
team found that in chronic sufferers who failed to respond
to treatment, the activity of at least four genes in the
body's nasal immune defense system were severely decreased,
and their production of two proteins critical to this
defense was 20 to 200 times less than normal.
Comparing nasal epithelial cell samples from nine
patients who benefited from surgery with nine who did not,
the Johns Hopkins team discovered suppressed levels of
human beta defensin 2 and mannose binding lectin in those
whose symptoms returned. The proteins are naturally
produced in the nose whenever the immune system detects
foreign bacteria or fungi, binding to invading pathogens,
inactivating them and making them easily disposed of.
An earlier study published by the same team in the
March-April issue of the American Journal of
Rhinology also showed that sinus tissue from people
with chronic sinusitis that resisted treatment had 30 times
lower than normal activity of a so-called toll-like
receptor gene, TLR9.
Inside the nose, researchers say, toll-like receptor
proteins detect invading bacteria and other pathogens in
the air by attaching to their trace by-products. Once a
threat is identified, the receptors stimulate the
epithelial cells to produce antibiotic proteins, such as
human beta defensin 2 and mannose binding lectin, to fight
the invading organisms. This innate response helps prevent
airborne bacteria or fungi from settling in the nose and
sinus cavities, causing infection.
"Colonization with microorganisms is a common problem
in patients with chronic sinusitis and polyps, but the
reasons for this are incompletely understood," said Andrew
Lane, an associate professor at the Johns Hopkins School of
Medicine and director of its rhinology and sinus surgery
center. "Now we are uncovering new clues as to what might
be wrong and perhaps, ultimately, how it might be
treated.
"The nose's first line of defense is the epithelium,
and when the local innate immune function is curtailed,
infections can get a head start, which might serve to
worsen the sinus inflammation," he said. "The potential is
there to manipulate these chemical receptors and proteins
to see if this makes patients more responsive to
conventional therapy."
The study, led by Lane, was believed to be the first
to determine levels of each toll-like receptor protein
— there are 10 — by directly measuring
messenger RNA expression in patients with and without
sinusitis patients. Scientists have known for more than a
year that toll-like receptor proteins were present in both
the healthy and sinusitis-wracked nose but not which
receptors or proteins were more important than others in
the condition's chronic form.
That study involved 30 men and women, mostly from the
Baltimore region, who had surgery for chronic sinusitis at
Johns Hopkins. (Another 10 had no sinus problem and served
as study controls.)
Those who underwent surgery did so after standard
therapy using antibiotics, decongestants and steroids had
failed to stop their symptoms and keep their infections
from coming back. Indeed, 20 participants in the study had
developed nasal polyps, which have no known cause and are
especially hard to treat, researchers say. Polyps must
often be surgically removed to allow the sinuses to drain
normally.
All patients were monitored for a minimum of six
months to see if any symptoms or polyps returned. Thirteen
in the surgery group had recurrent inflammation within
three months to one year after surgery, while the rest
remained symptom-free.
The Johns Hopkins team took samples during surgery of
the mucous membrane lining the nose, and using real-time
polymerase chain reaction, analyzed the samples for any
genetic differences between the groups.
"Surgically treating sinusitis is much like plumbing,
in the sense that we try to restore normal sinus cavity
drainage pathways," said study presenter Murugappan
Ramanathan Jr., a resident in
otolaryngology-head and neck surgery at Johns Hopkins.
"But for the intractable cases, surgery may fail because
the problem is not so much about plumbing as it is
inflammation, and for this we need research at the
molecular level to find a solution."
Funding for this study was provided in part by the
National Institutes of Health, including the National
Institute on Deafness and Other Communication Disorders,
and the National Institute of Allergy and Infectious
Diseases, with additional funding from the American
Rhinologic Society.
In addition to Lane and Ramanathan, researchers
involved in this research, conducted solely at Johns
Hopkins, were Quynh Ai Truong-Tran and Robert Schleimer.
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